This invention relates to the facilitation of wound healing in patients, by minimizing scarring and accelerating healing. This invention also relates to the reduction of wound-related tumor progression.
The normal process of healing a skin wound that has been surgically induced or is the result of trauma involves formation of a blood clot and, often, a scab. More particularly, first intention, or primary healing, generally occurs at clean incisions, whereas second intention, or secondary healing, occurs where wound edges are far apart. The protein fibrin holds the edges of the skin surrounding the wound together and the scab seals the wound and staves off infection. While an inflammatory response brings increased numbers of blood cells to the area to aid in the repair process, epithelial tissue regenerates and capillaries grow from blood vessels at the edges of the wound. The capillaries revascularize the area of the wound and contribute to the formation of granulation tissue which, in turn, causes scarring.
Granulation tissue begins to form in the wound site and fills the site approximately five days after wound induction. Granulation tissue contains new collagen, fibroblasts, new blood vessels and inflammatory cells, especially macrophages (E. Rubin and J. L. Farber, Pathology, Lippincott, publ., pp. 85-95 (1994)). After seven to ten days, the wound has regained only 10% of the tissue""s original strength.
Secondary healing causes a greater inflammatory response and more granulation tissue is formed. In addition, contraction of the wound, resulting from contraction of the fibroblasts of the granulation tissue, brings the edges of the wound together to speed the healing process, but sometimes contributes to disfiguring and debilitating scars. Additionally, excessive deposition of extracellular matrix leads to the formation of keloids, or hypertrophic scars, which are irregularly-shaped, elevated scars that tend toward progressive enlargement.
Angiogenesis is generally believed to be a necessary feature of repair (Kovacs, E. et al., Fibrogenic cytokines and connective tissue production, FASEB J., 8:854-861 (1994). Numerous growth factors and cytokines, secreted first by platelets in response to coagulation and then by macrophages in response to hypoxia and lactic acidosis, stimulate angiogenesis (Shah, M. et al., The Lancet, 339:213-214 (1992)). Angiogenesis generally becomes visible at a microscopic level about four days after injury but begins two or three days earlier when new capillaries sprout out of preexisting venules and grow toward the injury in response to chemoattractants released by platelets and macrophages. In primarily closed wounds, sprouting vessels soon meet counterparts migrating from the other side of the wound and blood flow across the wound is reestablished. In unclosed wounds, or those not well closed, the new capillaries fuse only with neighbors migrating in the same direction, and a large amount of granulation tissue is formed instead.
In normal wound healing, the tissue surrounding a wound undergoes a degree of hypoxia and a concomitant increase in secretion of vascular endothelial growth factor, or VEGF, typically occurring one to two days following injury (Brown, L. F. et al., Expression of VPF (VEGF) by epidermal keratinocytes during wound healing, J. Exp. Med., 176:1375-79 (1992)). VEGF stimulates the rapid proliferation of blood vessel endothelial cells which results in the formation of densely sprouting capillaries. This rapid hypoxia-induced, VEGF-driven capillary formation stimulates infiltration of inflammatory cells and leads eventually to scarring.
While inflammation causes scarring, inflammation is also beneficial. Inflammatory cells release growth signals and lytic enzymes that are very important for repair. In fact, patients who receive anti-inflammatory agents often experience impaired healing due to inadequate inflammation at the site of a wound.
An important aspect of wound repair is the time involved. The rate at which a wound heals has implications for the prevention of infection and improvement of the overall health of the patient. Rapid, even healing without excessive contraction is a desirable result from a medical and cosmetic standpoint.
Furthermore, it is a recognized clinical phenomenon that surgery in a tumor patient may lead to tumor progression if the site of the surgical incision is in proximity to the site of the tumor. In addition, the surgical incisions show high susceptibility to metastatic implantation. (Murthy et al., Cancer, 64:2035-2044 (1989); Murthy et al., Cancer, 68:1724-1730 (1991); Schackert, H. K. et al., Int. J. Cancer, 44:177-81 (1989)). The stimulatory effect of wounds on tumors is manifested as accelerated growth of residual tumor near the site of surgical intervention, as well as an increased probability of metastatic implantation at the site of surgery. Furthermore, wounds located at the site of a tumor regularly fail to heal (Gatenby, R. A. et al., Suppression of wound healing in tumor bearing animals, Cancer Research, 50:7997-8001 (1990)). Persistent wounds that continuously accelerate tumor progression may be a frequent side effect of surgical interventions associated with cancer therapy. Therefore, deciding whether to operate on a tumor patient is often a difficult decision in which the benefits of surgery must be compared to the risks of worsening a cancer patient""s overall condition.
It is an object, therefore, of the present invention to provide a method of preventing or minimizing scar formation during the wound healing process.
Another object of the present invention is to provide a method of accelerating the rate at which a wound heals.
A further object of the present invention is to provide a method of facilitating wound healing in tumor patients and minimizing the likelihood of tumor progression.
The method of the present invention provides for treating a patient having a wound by administering CM101, a generally nontoxic polysaccharide isolated from group B xcex2-hemolytic Streptococcus (GBS) bacteria, to minimize scarring and to accelerate wound healing. The invention finds use in treatment of surface as well as internal wounds.
Another aspect of the present invention is a method for treating a keloid by excising the keloid and administering CM101.
The present invention also provides a method of minimizing the likelihood of tumor progression, i.e. wound-induced tumor proliferation or metastatic implantation by administration of CM101 before, during and/or after surgery or other induction of a wound in a tumor patient.
An article of manufacture including GBS toxin, and particularly CM101, along with instructions for treatment, and a method of making the article are also disclosed.